1. Field
This invention relates generally to immediate release fenofibrate dosage forms.
2. Description of Related Art
Fenofibrate is an active principle which is very poorly soluble in water, and the absorption of fenofibrate in the digestive tract is limited. An increase in its solubility leads to better digestive absorption. Various approaches have been explored in order to increase the solubility of fenofibrate, including micronization of the active principle, addition of a surfactant, and comicronization of fenofibrate with a surfactant.
Fenofibrate is freely soluble in methanol and acetonitrile, and insoluble in water. Having no ionizable group, fenofibrate solubility is not influenced by changes in medium pH. However, the aqueous solubility of Fenofibrate can be improved in the presence of surfactants. As the concentration of the surfactant sodium lauryl sulfate, for example, increases from 0.0 M to 0.1 M, fenofibrate solubility increases from 0.8 mg/L to 910.8 mg/L.
There are various lipid regulating agents, such as atorvastatin, cerivastatin, ezetimibe, fluvastatin, lovastatin, pitavastatin, pravastatin, probucol, rosuvastatin, simvastatin and fibrates. The fibrates are a group of drugs which are known as hypolipidaemic agents. They include benzafibrate, clofibrate, ciprofibrate, fenofibrate and gemfibrozil. The fibrates have the beneficial effect of lowering cholesterol levels in the blood and hence reducing the risk of coronary heart disease.
Fenofibrate is a fibric acid derivative that has been marketed since the mid 1970's (1998 in the United States) as a lipid regulating drug. The chemical name of fenofibrate is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propionic acid, 1-methyl ester. It has a molecular formula C20H21O4Cl and a molecular weight of 360.83. The melting point of fenofibrate is 79° C. to 82° C. Fenofibrate is a white solid that is stable under ordinary conditions. Fenofibrate is absorbed as fenofibric acid, which is responsible for the pharmacological activity.
Fenofibrate has an extremely low solubility in water of around 6 micrograms/ml. This can adversely affect absorption of drugs of the drug substance in vivo, leading to poor bioavailability. Consequently higher amounts of the drug substance are required to achieve the desired blood levels. The poor solubility of the fenofibrate also restricts the options available for formulating the drug substance.
The standards for bioavailability and/or bioequivalence depend on several natural log transformed parameters associated with the rate and extent of absorption. Specifically, the rate and extent of absorption is measured by the parameters AUCL, AUCI, and Cmax. The parameter AUCL is the area under the plasma concentration-time curve from time zero to time t, where t is the last time point with measurable concentration for individual formulation. The parameter AUCI is the area under the plasma concentration-time curve from time zero to time infinity. Additionally, Cmax, sometimes referred to as Cpeak, is the maximum plasma concentration of the drug. For two products to be bioequivalent, the 90% confidence interval of the relative mean Cmax, AUCL, and AUCI of the test product to reference product should be within 80% to 125%.
Many methods have been used to enhance dissolution rates of poorly water-soluble or insoluble drugs in general, and fenofibrate in particular. Such methods include micronization of fenofibrate, microcrystallization of fenofibrate, preparation solid fenofibrate dispersions, and coprecipitation of fenofibrate with inert, water-soluble compounds as carriers. Other methods include grinding fenofibrate with an inert water-insoluble compound, so that fenofibrate is adsorbed onto the inert compound.
European Patent EP 256933 teaches fenofibrate granules which contain micronized fenofibrate. The crystalline fenofibrate particles are less than 50 microns in size. The micronized fenofibrate may be granulated with various types of binder polymers, such as polyvinylpyrrolidone, methacrylic polymers, cellulose derivatives, and polyethylene glycols, where an organic solvent is used for the granulation.
European Patent EP 330532 teaches improving the bioavailability of fenofibrate by comicronizing fenofibrate with a solid wetting agent or surfactant, such as sodium lauryl sulfate. The comicronizate is then granulated by wet granulation in order to improve the flow capacities of the powder and to facilitate filling into gelatin capsules. The comicronizate may be granulated with excipients such as lactose, starch, polyvinyl pyrrolidone and/or magnesium stearate. A formulation of the composition described in EP 330532 was compared to the formulation described in patent EP 256933, discussed above, and found to show a statistically significant increase in bioavailability vs. the formulation of EP 256933. Specifically, 67 mg fenofibrate in the formulation of EP 330532 gave the same absorption in vivo as 100 mg fenofibrate of the formulation of EP 256933. Therefore, the process described in EP 330532 led to a new dosage form in which the active ingredient, co-micronized with a solid surfactant, was able to show improved dissolution, and thus increased bioavailability, which makes it possible, for a given level of effectiveness, to decrease the daily dose of the medicament.
U.S. Pat. No. 4,895,726 teaches to improve fenofibrate bioavailability using a composition containing a comicronized mixture of particles of fenofibrate and a solid surfactant. The co-micronization was carried out in an accelerated air-jet mill until the powder obtained has a mean particle size is less than 15 microns. The powder was mixed with lactose and starch and granulated. The dried granules were mixed with polyvinylpyrrolidone and magnesium stearate and filled in gelatin capsules. U.S. Pat. No. 4,895,726 teaches that there is no statistically significant difference between the in vivo bioavailability of 200 mg of co-micronized fenofibrate according to the invention of U.S. Pat. No. 4,895,726 and 300 mg of non-micronized fenofibrate. In other words, this patent proved that co-micronized fenofibrate at a 200 mg dose is bioequivalent to a 300 mg dose of a non-micronized fenofibrate formulation according to EP 330532.
U.S. Pat. No. 4,800,079 describes a granular medicine based on fenofibrate, each granule comprising an inert core, a layer based on fenofibrate, and a protective layer. The medicine is characterized in that the fenofibrate is present in the form of crystalline microparticles having a size of less than 30 microns, and preferably less than 10 microns. The layer based on fenofibrate includes a binder selected from the group consisting of methacrylic polymers, polyvinylpyrrolidone, cellulose derivatives, and polyethylene glycols.
U.S. Pat. No. 7,101,574 describes a pharmaceutical composition in the form of granules, containing neutral microgranules, supporting a layer of a composition comprising micronized fenofibrate, a surfactant and, a cellulose binding cellulose derivative, preferably hydroxypropylmethylcellulose (HPMC), as a solubilizing adjuvant. The cellulose derivative represents less than 20 wt. % of the composition, while the fenofibrate is present in an amount greater than or equal to 60% by weight of the pharmaceutical composition. The pharmaceutical composition reported in U.S. Pat. No. 7,101,574 describes the fenofibrate:HPMC mass ratio as being between 5:1 and 15:1. The formulation disclosed in U.S. Pat. No. 7,101,574 provides enhanced bioavailability of the active principle. U.S. Pat. No. 7,101,574 compares the in vivo release profile of gelatin capsules containing the disclosed granules to gelatin capsules containing an equivalent dose of the formulation of EP 330532, marketed under the trade name Lipanthyl 200M. The maximum plasma concentration (Cmax) of the disclosed formulation under fasting conditions was reported to be 4.71 microgram/mL, compared to a Cmax of 2.35 microgram/mL attained with the formulation of EP 330532.
This present disclosure provides a formulation having a higher bioavailability than commercially available products containing fenofibrate, including ANTARA® Capsules, sold by Lupin Laboratories and containing 130 mg of fenofibrate. The ANTARA® Capsules are made according to the teachings of U.S. Pat. No. 7,101,574 and/or 7,863,331.
In various embodiments, the formulation of the present disclosure comprises Fenofibrate or a related drug, HPMC, a surfactant, such as sodium lauryl sulfate, an inert support, such as sugar spheres (20-45 mesh or 850-355 microns) and other excipients. In various embodiments, the inert supports may have a size of 35-45 mesh or 500-355 microns). In other embodiments, the inert supports may have a size of 20-25 mesh or 850-710 microns). The fenofibrate to HPMC weight ratio is between about 3.5:1 and about 4.5:1, and the amount of sodium lauryl sulfate is between about 0.3% and about 10% by weight. The fenofibrate formulation and method of manufacturing disclosed herein provides an improvement in Cmax, compared to ANTARA® capsules. In various embodiments, the fenofibrate formulation and method of manufacturing disclosed herein provides an improvement in Cmax without significantly affecting values for AUCL and/or AUCI, when compared to ANTARA® capsules. Various embodiments disclosed herein may afford an improvement in Cmax and an increase in AUCL and/or AUCI, compared to ANTARA® capsules.